August 7, 2014. Researchers took a fresh look at the dopamine hypothesis of schizophrenia in an afternoon SIRS session on Monday, April 7. There is a conception in the field that when it comes to excess dopamine in schizophrenia, "all the action is in the mesolimbic pathway," said chair and discussant Anissa Abi-Dargham, Columbia University, New York City. Historically, researchers have focused on the ventral striatum, but a lot is going on in the dorsal or "associative" region of the structure, she continued. Recent positron emission tomography studies find that the associative striatum has the greatest dopamine excess, and suggest that it is also where dopaminergic abnormalities first appear during the prodromal period (see SRF related news report; SRF news report).

Columbia University's Tiziano Colibazzi presented multimodal imaging evidence suggesting that at baseline, individuals at clinical high risk for development of psychosis have aberrant connectivity between the associative striatum and the dorsolateral prefrontal cortex (DLPFC). Specifically, he reported that high-risk subjects exhibited low fractional anisotropy, indicative of disorganized fiber tracts, in connections between the striatum and the frontal cortex. Functional connectivity analyses indicated a higher degree of centrality in the thalamus of high-risk subjects—meaning that there are more connections to and from the thalamus in these subjects than in controls—and increased connectivity between the ventral rostral putamen and thalamus. In a cognitive control task in which subjects must inhibit a response in order to perform a goal-directed behavior, high-risk subjects displayed hyperactivity in the dorsal and ventral striatum and hypoactivity in the DLPFC.

Camilo de la Fuente-Sandoval, from Mexico City's Instituto Nacional de Neurologia y Neurocirugia, discussed proton magnetic resonance spectroscopy findings in a cohort at high risk for psychosis. He reported elevated levels of associative striatum glutamate at baseline in these subjects, similar to findings in antipsychotic-naive first-episode patients. A subsequent measurement after two years revealed that those who transitioned to psychosis had higher levels of glutamate at baseline. GABA levels, as well as a combined measure of glutamate and glutamine, were also elevated in the associative striatum in a second cohort of high-risk subjects.

Oliver Howes, King's College London, United Kingdom, reviewed data on the elevated striatal dopamine synthesis capacity in the psychosis prodrome (see SRF related news report; SRF news report). The elevation is found only in the associative striatum, not in other striatal subdivisions, and is specific to those who later convert to schizophrenia. In addition, the elevated dopamine synthesis capacity is also observed in the substantia nigra, which projects to the associative striatum. Howes then discussed several possible methodological caveats for these observations and wondered if the results could be an artifact of volume differences or measurement variability in different striatal regions.

In the only animal studies of the session, Bita Moghaddam, University of Pittsburgh, Pennsylvania, presented data suggesting that the associative striatum in rats is "uniquely different in adolescents compared to adults." This is surprising, she said, because this region has always been used as a control region. In contrast to adults, adolescents show very robust dorsal striatum activation in response to reward. In the nucleus accumbens, on the other hand, neural activity is similar between adolescents and adults.

In addition, studies using amphetamine show that dopamine release in the adolescent dorsal striatum is blunted, said Moghaddam. This hypoactivity may be the result of the reduced levels of tyrosine hydroxylase (TH)—the enzyme that synthesizes dopamine—that are present in the dorsal striatum of adolescent rats. These data suggest that reduced striatal activity may be a normal component of adolescent development that is disrupted in those especially vulnerable to schizophrenia, Moghaddam added. The adolescent dorsal striatum is also sensitive to a dietary deficiency in omega-3 fatty acid, which has been implicated in schizophrenia, she said, citing decreased levels of TH in a rat model of omega-3 fatty acid deficiency (Bondi et al., 2014).

The bottom line from the session, concluded Abi-Dargham, is that "the associative striatum is one of the earliest structures that shows alterations" in the process of moving from the ill-defined high-risk state to psychosis. It is interesting that dopamine, glutamate, and GABA are all increased in this one structure, she added.—Allison A. Curley.

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